Transcriptional regulation plays a critical role in normal cell and organ differentiation, development and physiology in humans. Not surprisingly, up or downregulation of transcription factors and their coregulators has been tightly linked to tumor development and the progression to malignant and metastatic stages. Cancer cells originate primarily from epithelial tissues. Accumulating evidence suggests that during cancer progression, cells begin to redistribute or downregulate proteins involved in maintaining cell adherens and tight junctions. These changes and others promote a loss of cell-cell and cell-matrix interactions and permit cell motility and invasion of neighboring tissues. While approximately 90% of all cancer deaths occur because of tumor metastasis, very few therapies are available that are effective in preventing metastasis. One way to overcome this limitation is to gain a complete understanding of the genetic and signaling networks that promote and modulate tumor cell motility and metastasis. The Thanatos associated protein (THAP) family is comprised of 12 members in the human, and only 3 members have been partially characterized. Recently we observed that THAP11, a member of the THAP family is differentially expressed in cancer cells. How THAP11 overexpression contributes to cancer cell function is completely unknown and thus represents an exciting and novel field of investigation. Based on our preliminary results, we hypothesize that THAP11 is a transcriptional repressor that plays a critical role in cancer cell function by directly regulating expression of key genes involved in intercellular and cell-matrix interactions. Since alteration of these interactions is a key initial event in metastasis, we propose that THAP11 represents a novel and critical transcriptional regulator of cancer cell function. We will undertake state-of-the-art molecular, cellular, physiologic and genome-wide analyses to define the impact of THAP11 overexpression and its mechanism of action in cancer cell function in three integrated specific aims. The proposed studies will greatly advance our knowledge of cancer progression and metastasis, and may provide a molecular target for therapeutic intervention. PUBLIC HEALTH RELEVANCE: While approximately 90% of all cancer deaths occur because of tumor metastasis, very few therapies are available that are effective in preventing metastasis. One way to overcome this limitation is to gain a complete understanding of the genetic and signaling networks that promote and modulate tumor cell motility and metastasis. In this work, we will determine the role of a novel human protein termed THAP11 in cancer cell function. The proposed studies will greatly advance our knowledge of cancer progression and metastasis, and may provide a molecular target for therapeutic intervention.